Phenoxypropanolamines, method for producing them and pharmaceutical compositions containning them

ABSTRACT

The invention relates to compounds of formula (I)  
                 
 
     where  
     R 1  represents a hydrogen or halogen atom or an —S(O) z —(C 1 -C 4 )alkyl, —S(O) z —(C 1 -C 4 )R 3 , —SO 2 —NH—(C 1 -C 4 )alkyl, —NHCO(C 1 -C 4 ) alkyl, —CO(C 1 -C 4 )alkyl or —NHSO 2 —(C 1 -C 4 )alkyl group;  
     m and n independently represent 0, 1 or 2;  
     A represents a group of formula (a) or (b):  
                 
 
     where  
     X is N or CH;  
     R 2  represents an —SO 2 —R 3 , —CO—R 3  or —CO—(C 1 -C 4 )—alkyl group;  
     R 3  represents a phenyl group, optionally substituted by a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, one or two halogen atoms or a heterocycle;  
     R 4  represents a hydrogen or halogen atom or a (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, —COOH, —COO(C 1 -C 4 )alkyl, —CN, —CONR 5 R 6 , —NO 2 , —NHSO 2 (C 1 -C 4 )alkyl or —SO 2 NR 5 R 6  group;  
     z is 1 or 2;  
     R 5  and R 6  independently represent a hydrogen atom or a (C 1 -C 4 )alkyl, phenyl or phenyl (C 1 -C 4 )alkyl group;  
     and their salts or solvates, to a process for their preparation, to synthetic intermediates and to the pharmaceutical compositions comprising them.

[0001] The present invention relates to novel phenoxypropanolamines, tothe pharmaceutical compositions comprising them, to a process for theirpreparation and to intermediates in this process.

[0002] BE 902897 discloses aryloxypropanolamines carrying a(4-piperidinin-1-yl)-substituted group on the amine, these compoundshaving a beta-1-blocking and alpha-blocking activity.

[0003] J. Org. Chem., 1988, 63, 889-894, describes otheraryloxypropanolamines carrying a (4-piperidin-1-yl)-substituted group onthe amine.

[0004] It has now been found that novel phenoxypropanolamines carrying a(4-piperidin-1-yl)-substituted [lacuna] on the amine have an agonistactivity with respect to beta-3-adrenergic receptors.

[0005] The beta-3-adrenergic receptor has formed the subject of numerousstudies targeted at synthesizing compounds which are agonists withrespect to this receptor, these compounds exerting a significantantiobesity and antidiabetic effect in man, as described, for example,by Weyer, C et al., Diabetes Metab., 1999, 25(1), 11-21.

[0006] Thus, the present invention relates, according to one of itsaspects, to phenoxypropanolamines of formula (I)

[0007] where

[0008] R₁ represents a hydrogen or halogen atom or an—S(O)_(z)—(C₁-C₄)alkyl, —S(O)_(z)—(C₁-C₄)R₃, —SO₂—NH—(C₁-C₄)alkyl,—NHCO(C₁-C₄)alkyl, —CO(C₁-C₄)alkyl or —NHSO₂—(C₁-C₄)alkyl group;

[0009] m and n independently represent 0, 1 or 2;

[0010] A represents a group of formula (a) or (b):

[0011] where

[0012] x is N or CH;

[0013] R₂ represents an —SO₂—R₃, —CO—R₃ or —CO—(C₁-C₄)— alkyl group;

[0014] R₃ represents a phenyl group, optionally substituted by a(C₁-C₄)alkyl or (C₁-C₄)alkoxy group, one or two halogen atoms or aheterocycle;

[0015] R₄ represents a hydrogen or halogen atom or a (C₁-C₆)alkyl,(C₁-C₄)alkoxy, —COOH, —COO(C₁-C₄)alkyl, —CN, —CONR₅R₆, —NO₂,—NHSO₂(C₁-C₄)alkyl or —SO₂NR₅R₆ group;

[0016] z is 1 or 2;

[0017] R₅ and R₆ independently represent a hydrogen atom or a(C₁-C₄)alkyl, phenyl or phenyl(C₁-C₄)alkyl group;

[0018] and their salts or solvates.

[0019] In the present description, the terms “(C₁-C₄)alkyl” and“(C₁-C₆)alkyl” denote monovalent radicals of a respectively C₁-C₄ andC₁-C₆ hydrocarbon comprising a straight or branched saturated chain.

[0020] In the present description, the term “halogen” denotes an atomchosen from chlorine, bromine, iodine and fluorine.

[0021] The salts of the compounds of formula (I) according to thepresent invention comprise both addition salts with pharmaceuticallyacceptable inorganic or organic acids, such as the hydrochloride,hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, citrate,maleate, tartrate, fumarate, gluconate, methanesulfonate,2-naphthalenesulfonate, and the like, and addition salts which makepossible suitable separation or crystallization of the compounds offormula (I), such as the picrate, the oxalate or the addition salts withoptically active acids, for example camphorsulfonic acids and mandelicor substituted mandelic acids.

[0022] When the compounds of formula (I) possess a free carboxyl group,the salts also comprise the salts with inorganic bases, preferably thosewith alkali metals, such as sodium or potassium, or with organic bases.

[0023] The optically pure stereoisomers and the mixtures of isomers ofthe compounds of formula (I), due to the asymmetric carbons or to thesulfinyl group, when z is 1 in the meaning of R₁, in any proportion,form part of the present invention.

[0024] Preferred compounds are those where the (C₁-C₄)alkyl group is amethyl or ethyl group.

[0025] Other further preferred compounds are those where n and m arezero.

[0026] Preferred compounds of the present invention comprise thecompounds of formula (I) where A is a group (a), X is N and the NHR₂group is in the 5 position of the pyridine.

[0027] Other preferred compounds of the present invention comprise thecompounds of formula (I) where A is a group (b) and the R₄ group is inthe 4 position of the benzene.

[0028] Other preferred compounds are those where A is a group (b) and R₄is chosen from —COOH, —COO(C₁-C₄)— alkyl, —CN, —NO₂, —CONR₂R₃,—NHSO₂—(C₁-C₄)alkyl or —SO₂NR₅R₆.

[0029] The compounds of formula (I) can be prepared by treating acompound of formula (II)

[0030] in which R₁ is as indicated above, P′ is a protective group and Lis a group of formula (c) or (d)

[0031] where Gp is a leaving group, such as tosylate, mesylate or ahalogen atom, with an amine of formula (III)

[0032] in which n and m are as defined above, the group P′ being cleavedaccording to conventional methods and the compound of formula (I) thusobtained optionally being converted into one of its salts.

[0033] More particularly, the reaction between the compounds of formula(II) and (III) is carried out in an organic solvent, such as a loweralcohol, for example methanol, ethanol and isopropanol; dimethylsulfoxide; a linear or cyclic ether; or an amide, such asdimethylformamide or dimethylacetamide; using at least equimolecularamounts of the reactants, optionally in a slight excess of amine.

[0034] The temperature of the reaction is between ambient temperatureand the reflux temperature of the solvent chosen.

[0035] Use may be made, as protective groups P′, of the conventionalprotective groups for hydroxyl groups, such as, for example,methoxyethoxymethyl (MEM), benzyl, benzoyl or silyl ethers, such as, forexample, the tert-butyldimethylsilyl ether (TBDMS).

[0036] The cleaving of these protective groups is carried out accordingto the standard methods according to the protective group chosen andaccording to the reactivity of the other groups present, in the case ofthe benzyl group, for example, by hydrogenation in the presence of acatalyst, such as Pd/C, in a suitable solvent; in the case of MEM or ofTBDMS, it is also possible to use an acid, such as trifluoroacetic acid;in the case of benzoyl, a transesterification reaction with an alkanolin a basic medium can be carried out.

[0037] The epoxides of formula (II) are compounds which are known in theliterature or alternatively they can be prepared by processes analogousto those described in the literature. Some epoxides of formula (II) are,for example, disclosed in WO 96/04233 and in U.S. Pat. No. 4,396,629.

[0038] Some of the amines of formula (III) are novel compounds andconstitute another aspect of the present invention.

[0039] Thus, according to another of its aspects, the present inventionrelates to amines of formula (III′)

[0040] where n, m, X and R₂ are as defined above, and their salts orsolvates.

[0041] These amines can be prepared by reaction of the compounds offormula (IV)

[0042] in which P″ is a protective group, such as tert-butoxy-carbonylor benzyloxycarbonyl, with a radical Cl—R₂, where R₂ is as describedabove and Hal is a halogen atom, in a suitable solvent, such as, forexample, pyridine, dimethylformamide or dimethyl sulfoxide, and byremoval of the group P″ by hydrogenation or by treatment in an acidicmedium, such as hydrochloric acid in ethyl acetate or in ethanol.

[0043] The starting amines of formula (IV) can be prepared by reactionof suitable pyridines of formula (V)

[0044] where Hal represents a halogen atom and R₂ and m are as definedabove, with a piperidine of formula (VI) below

[0045] where n is as defined above and P″ represents a protective group,in an organic solvent in the presence of a base.

[0046] Use may indeed be made, as reaction solvent, of, for example,dimethylformamide, pyridine, dimethyl sulfoxide, a linear or cyclicether, or a chloridated solvent, such as dichloromethane.

[0047] Use may be made, as base, of, for example, an alkaline hydroxide,an alkaline carbonate, such as potassium carbonate, or a tertiary amine,such as triethylamine.

[0048] The above condensation reaction is completed in a few hours,normally in 2-12 hours.

[0049] The reaction temperature is between ambient temperature and thereflux temperature of the solvent chosen.

[0050] Use may be made, as protective groups P″, of, for example, theprotective groups indicated for the products of formula (IV).

[0051] The cleaving of these protective groups is carried out accordingto the standard methods described [lacuna] the protective group chosen;in the case of tert-butoxycarbonyl, for example, the cleaving isnormally carried out by acid hydrolysis.

[0052] Other novel intermediates which form part of the presentinvention are the amines of formula (III″)

[0053] where

[0054] P^(°) is a tert-butoxycarbonyl group;

[0055] n and m are 0, 1 or 2;

[0056] R°₄ is a group chosen from —COOH, —COO(C₁-C₄)— alkyl, —CONR°₅R°₆and —NHSO₂(C₁-C₄)alkyl; R°₅ and R°₆ independently represent a hydrogenatom or a (C₁-C₄)alkyl group;

[0057] and their salts or solvates.

[0058] Compounds of formula (III″) which are particularly preferred arethose where n is 0, m is 0 or 1 and R°₄ is —COO(C₁-C₄)alkyl.

[0059] The compounds of formula (III″) can be prepared analogously tothe above compounds (IV).

[0060] The compounds of formula (I) have shown a very powerful affinitywith respect to beta-3 receptors.

[0061] The activity of the compounds of the present invention withrespect to beta-3 agonist activity was demonstrated using in vitro testson the human colon according to the method disclosed in EP-B-436 435 andin T. Croci et al., Br. J. Pharmacol., 1997, 122, 139P.

[0062] More particularly, it has been found that the compounds offormula (I) are much more active on the isolated colon than on theatrium and on the trachea.

[0063] These surprising properties of the compounds of formula (I) makeit possible to envisage their use as medicaments with a beta-3 action.

[0064] Furthermore, the compounds of formula (I) are not very toxic; inparticular, their acute toxicity is compatible with their use asmedicaments for the treatment of diseases in which compounds having anaffinity for the beta-3 receptor find application. The compounds offormula (I) and their pharmaceutically acceptable salts can therefore beindicated, for example, in the treatment of gastrointestinal diseases,such as irritable bowel syndrome (IBD), as modulators of intestinalmotricity, or as lipolytics, antiobesity agents, antidiabetics,psychotropics, antiglaucoma agents, cicatrizants, antidepressants ortocolytics.

[0065] The use of the compounds of formula (I) above, and that of theirpharmaceutically acceptable salts and solvates, for the preparation ofabove medicaments constitutes a subsequent aspect of the presentinvention.

[0066] For such a use, an effective amount of a compound of formula (I)or of one of its pharmaceutically acceptable salts and solvates isadministered to the mammals who require such a treatment.

[0067] The compounds of formula (I) above and their pharmaceuticallyacceptable salts and solvates can be used at daily doses of 0.01 to 20mg per kilo of body weight of the mammal to be treated, preferably atdaily doses of 0.1 to 10 mg/kg. In man, the dose can preferably varyfrom 0.5 mg to 1 500 mg per day, in particular from 2.5 to 500 mg,according to the age of the subject to be treated, the type oftreatment, prophylactic or curative, and the seriousness of thecondition. The compounds of formula (I) are generally administered as adosage unit of 0.1 to 500 mg, preferably of 0.5 to 100 mg, of activeprinciple, one to five times daily.

[0068] Said dosage units are preferably formulated in pharmaceuticalcompositions in which the active principle is mixed with apharmaceutical excipient.

[0069] Thus, according to another of its aspects, the present inventionrelates to pharmaceutical compositions including, as active principle, acompound of formula (I) above or one of its pharmaceutically acceptablesalts and solvates.

[0070] In the pharmaceutical compositions of the present invention fororal, sublingual, subcutaneous, intramuscular, intravenous, topical,transdermal or rectal administration, the active ingredients of formula(I) above and their pharmaceutically acceptable salts and solvates canbe administered in unit administration forms, as a mixture withconventional pharmaceutical vehicles, to animals and human beings forthe treatment of the above said conditions. The appropriate unitadministration forms comprise oral forms, such as tablets, gelatincapsules, powders, granules and solutions or suspensions to be takenorally, sublingual and buccal administration forms, subcutaneous,intramuscular or intravenous administration forms, local administrationforms and rectal administration forms.

[0071] When a solid composition is prepared in the form of tablets, themain active ingredient is mixed with a pharmaceutical vehicle, such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets can be coated with sucrose or other appropriatematerials or can be treated so that they have a prolonged or delayedactivity and so that they continuously release a predetermined amount ofactive principle.

[0072] A preparation in the form of gelatin capsules is obtained bymixing the active ingredient with a diluent and by pouring the mixtureobtained into soft or hard gelatin capsules.

[0073] A preparation in the syrup or elixir form can comprise the activeingredient in conjunction with a sweetener, preferably a calorie-freesweetener, methylparaben and propylparaben as antiseptics, and anappropriate colorant and flavoring.

[0074] The water-dispersible powders or granules can comprise the activeingredient as a mixture with dispersing agents, wetting agents orsuspending agents, such as polyvinylpyrrolidone, and with sweeteners orflavor enhancers.

[0075] For local administration, the active principle is mixed in anexcipient for the preparation of creams or ointments or is dissolved ina vehicle for intraocular administration, for example in the form of aneyewash.

[0076] For rectal administration, recourse is had to suppositories whichare prepared with binders which melt at the rectal temperature, forexample cocoa butter or polyethylene glycols.

[0077] For parenteral administration, use is made of aqueoussuspensions, saline solutions or sterile injectable solutions whichcomprise pharmacologically compatible dispersing and/or wetting agents,for example propylene glycol or butylene glycol.

[0078] The active principle can also be formulated in the form ofmicrocapsules, optionally with one or more vehicles or additives.

[0079] According to another of its aspects, the present inventionrelates to a method for the treatment of the pathologies which areimproved by a beta-3-agonist action which comprises administering acompound of formula (I) or one of its pharmaceutically acceptable saltsor solvates.

[0080] The compounds of formula (I), in particular the compounds (I)labeled with an isotope, can also be used as laboratory tools inbiochemical assays.

[0081] The compounds of formula (I) bind to the beta-3-adrenergicreceptor. These compounds can therefore be used in a standard bindingassay, in which use is made of an organic tissue in which this receptoris particularly abundant, and the amount of compound (I) displaced by atest compound is measured, in order to evaluate the affinity of saidcompound with respect to binding sites of this specific receptor.

[0082] Another specific subject matter of the present invention is thusa reagent which can be used in biochemical assays, which comprises atleast one suitably labeled compound of formula (I).

[0083] The examples which follow give a better illustration of theinvention.

[0084] Preparation 1

[0085] 4-(tert-Butoxycarbonylamino)piperidine.

[0086] 25 g (0.13 mol) of 4-amino-1-benzylpiperidine, 36.2 ml (0.26 mol)of triethylamine and 31.2 g (0.143 mol) of di-tert-butyl dicarbonate aremixed in 200 ml of dimethylformamide at ambient temperature for 2 hours.The mixture is poured into water, extraction is carried out with ethylacetate and washing is carried out with water, and the product thusobtained is crystallized from 200 ml of isopropyl ether. 33 g of1-benzyl-4-(tert-butoxycarbonylamino)piperidine are obtained and arehydrogenated in a mixture of 200 ml of ethanol and 100 ml oftetrahydrofuran in the presence of 3 g of 10% Pd/C. After filtering offthe catalyst, the title compound is isolated.

[0087] M.p. 157-160° C.

[0088] Preparation 2

[0089]4-tert-Butoxycarbonylamino-1-(4-ethoxycarbonylphenylmethyl)piperidine

[0090] A mixture of 2.01 g (0.010 mol) of the product obtained inpreparation 1 and 2 g (0.010 mol) of4-chloromethyl-ethoxycarbonylbenzene in 40 ml of dimethylformamide isheated with stirring for 6 hours at 50° C. The mixture is poured intowater, extraction is carried out with ethyl acetate and washing iscarried out with water. The product is filtered off and dried. The crudeproduct thus obtained is purified by flash chromatography, elution beingcarried out with a cyclohexane/ethyl acetate=1:1 mixture. The titlecompound is obtained.

[0091] M.p. 74-76° C.

[0092] Preparation 3

[0093] 4-Amino-1-(4-ethoxycarbonylphenylmethyl)piperidine

[0094] The product obtained by preparation 2 is heated at reflux for 5hours in a solution comprising 15 ml of ethyl acetate and 15 ml ofhydrochloric acid in ethyl acetate (about 3N). After cooling, filtrationis carried out, washing with acetone is carried out and the product isdried under reduced pressure. The title product is obtained inhydrochloride dihydrate form by crystallization from an ethanolsolution.

[0095] M.p. 290-293° C.

[0096] Preparation 4

[0097] 4-tert-Butoxycarbonylamino-1-(4-ethoxycarbonylphenyl)piperidine

[0098] 21.6 g (0.10 mol) of the product from preparation 1 are heated at80° C. for 55 hours with 9.06 g (0.01 mol) of(4-ethoxycarbonyl-1-fluoro)benzene and 14.9 g of K₂CO₃ in 200 ml ofdimethylformamide. The K₂CO₃ is filtered off, the solution is pouredinto water and extracted with ethyl acetate, and the solvent isevaporated. The crude reaction product is purified by flashchromatography, elution being carried out with a cyclohexane/ethylacetate=8:2 mixture. The title product is obtained and is crystallizedfrom ethyl acetate.

[0099] M.p. 138-140° C.

[0100] Preparation 5

[0101] 4-Amino-1-(4-ethoxycarbonylphenyl)piperidine Hydrochloride

[0102] 7.94 g (0.023 mol) of the product from preparation 4 aredissolved in 60 ml of ethyl acetate, and 80 ml of a 3N solution ofhydrochloric acid in ethyl acetate are added. The mixture is heated atreflux for 5 hours, the solvent is evaporated, acetone is added andfiltration is carried out. The title product is obtained and iscrystallized from ethanol.

[0103] M.p. 240-242° C. (hydrochloride)

[0104] Preparation 6

[0105] 4-tert-Butoxycarbonylamino-1-(4-methoxycarbonylphenyl)piperidine

[0106] 3 mg (0.01 mmol) of Pd(OAc)₂, 10 mg (0.015 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 215 mg (1.2 mmol)of 4-bromo-1-methoxycarbonylbenzene and 240 mg of the product frompreparation 1 (1.2 mmol) are added to a suspension of 456 mg of Cs₂CO₃in 2 ml of anhydrous toluene. The mixture is heated at 110C and, after 2days, 2 ml of dioxane, 3 mg of Pd(OAc)₂ and 10 mg of BINAP are added.The mixture is heated for a further two days at 1100 and then thereaction is halted. The mixture is poured into water and extracted withethyl acetate. The product is purified by flash chromatography, elutionbeing carried out with an ethyl acetate/cyclohexane mixture.

[0107] M.p. 162-165° C.

[0108] Preparation 7

[0109]4-(Phenylmethoxy)-3-(N-tert-butoxycarbonyl-N-methansulfonylamino)-1-(2,3-epoxypropoxy)benzeneand Its (2S) Isomer

[0110] The title product was obtained according to the proceduredisclosed in WO 96/04233 (procedure 96).

[0111] Preparation 8

[0112] 4-Benzyloxy-3-methylsulfinyl-1-[(2,3-epoxypropoxy)]-benzene

[0113] The title product was obtained following the procedure disclosedin U.S. Pat. No. 4,396,629.

[0114] Preparation 9

[0115] 4-Benzyloxy-1-[(2,3-epoxypropoxy)]benzene

[0116] The title product was obtained following the procedure disclosedin WO 96/04233 (procedure 7).

[0117] Preparation 10

[0118] 4-tert-Butoxycarbonylamino-1-(4-hydroxycarbonylphenyl)piperidine

[0119] 2.19 g (0.0063 mol) of the product from preparation 4 aredissolved in 30 ml of ethanol and 30 ml of THF, and 20 ml of water and12.6 ml (0.0126 mol) of a 1N NaOH solution are added thereto. Themixture is stirred at ambient temperature for 24 hours and then at 40°C. for 8 hours. Acetic acid is added until a pH of 5 is achieved and thesolvent is evaporated under reduced pressure. The residue is taken up inwater and the solid is filtered off and recrystallized from 200 ml ofethanol. The title product is obtained in the form of a white solid.M.p. >300° C.

[0120] Preparation 11

[0121] 4-Amino-1-[4-(N-normal-butylaminocarbonyl)phenyl]-piperidineHydrochloride Hydrate

[0122] 11a.4-tert-Butoxycarbonylamino-1-[4-(N-normal-butylaminocarbonyl)phenyl]piperidine

[0123] 2.5 g (0.0078 mol) of the product from preparation 10 aredissolved in 80 ml of methylene chloride, and 3.45 g (0.0078 mol) ofBOP, 8 ml (0.0078 mol) of normal-butylamine and 1.7 ml (0.012 mol) oftriethylamine are added thereto. The mixture is stirred at 40° C. for 8hours, the solvent is evaporated under reduced pressure, and the residueis taken up in ethyl acetate and washed with a saturated sodiumbicarbonate solution. The solid formed is filtered off and crystallizedfrom isopropanol. The title compound is obtained in the form of a whitesolid.

[0124] M.p. 208-210° C.

[0125] 11b. 4-Amino-1-[4-(N-normal-butylaminocarbonyl)phenyl]-piperidineHydrochloride Hydrate

[0126] By carrying out the operation as described in preparation 5 butusing the product from the preceding stage instead of the product frompreparation 4, the title compound is obtained.

[0127] M.p. 231-235° C. (hydrochloride hydrate)

[0128] Preparation 12

[0129] 4-Amino-1-[4-(N,N-diethylaminocarbonyl)phenyl]-piperidinedihydrochloride

[0130] 12a.4-tert-Butoxycarbonylamino-1-[4-(N,N-diethylaminocarbonyl)phenyl]piperidine

[0131] By carrying out the operation as described in preparation 11a butusing diethylamine instead of normal-butylamine, the title compound isobtained.

[0132] M.p. 113-115° C.

[0133] 12b. 4-Amino-1-[4-(N,N-diethylaminocarbonyl)phenyl]-piperidineDihydrochloride

[0134] By carrying out the operation as described in preparation 11b butusing the product from the preceding stage instead of the product frompreparation 11a, the title compound is obtained.

[0135] M.p. 232-234° C. (dihydrochloride)

[0136] Preparation 13

[0137]4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-(butansulfonyl)amino)-1-[((2S)-2,3-epoxypropoxy)]benzene

[0138] 13a. 4-Benzyloxy-3-(butansulfonylamino)benzene Acetate

[0139] 5.0 g (0.00194 mol) of 3-amino-4-benzyloxybenzene acetate aremixed under a nitrogen atmosphere in 15 ml of methylene chloride, and3.3 ml of triethylamine (0.0236 mol) and 3.3 ml (0.0245 mol) of1-butansulfonyl chloride are added thereto. The mixture is stirred atambient temperature overnight and afterwards at 30° C. for 4 hours.Washing with water is carried out, the two phases are separated, theorganic phase is dried over sodium sulfate and filtered, and the solventis evaporated under reduced pressure. Purification is carried out bychromatography on a column of silica gel, elution being carried out witha cyclohexane/ethyl acetate=9:1 mixture. The title compound is obtained.

[0140] M.p. 104-106° C.

[0141] 13b.4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-(butansulfonyl)amino)benzeneAcetate

[0142] 3.4 g (0.009 mol) of the product from the preceding stage aremixed in 70 ml of methylene chloride, and 2.4 g (0.0108 mol) ofdi-tert-butyl dicarbonate and 0.22 g (0.0018 mol) of4-dimethylaminopyridine are added thereto. The mixture is stirred atambient temperature for 3 hours, the solvent is evaporated and theresidue is purified by chromatography on a column of silica gel, elutionbeing carried out with a cyclohexane/ethyl acetate=8:2 mixture. Thetitle compound is obtained.

[0143] M.p. 74-76° C.

[0144] 13c.4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-(butansulfonyl)amino)phenol

[0145] 4 g (0.0083 mol) of the product from the preceding stage aremixed in 80 ml of methanol, and 9.9 g (0.0099 mol) of 1N NaOH are addedthereto. The mixture is stirred at ambient temperature for 30 minutes,citric acid is added until a pH of 6 is achieved and the solvent isevaporated. The residue is taken up with ethyl acetate, washing withwater is carried out, the two phases are separated, the organic phase isdried over sodium sulfate and filtered, and the solvent is evaporatedunder reduced pressure. The title compound is obtained.

[0146] M.p. 131-133° C.

[0147] 13d.4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-(butansulfonyl)amino)-1-[((2S)-2,3-epoxypropoxy)]-benzene

[0148] 3.0 g (0.0062 mol) of the product from the preceding stage aremixed in 60 ml of acetone, and 2.8 g of ground anhydrous potassiumcarbonate and 2.0 g (0.0077 mol) of (2S)-(+)-glycidyl nosylate are addedthereto. The mixture is heated at reflux for 20 hours and filtered, thesolvent is evaporated and the residue is purified by chromatography on acolumn of silica gel, elution being carried out with a cyclohexane/ethylacetate=75/25 mixture. The title compound is obtained.

[0149] M.p. 87-89° C.

[0150] [α]_(D)=+4.9° C. (c, 1% in methanol)

[0151] Preparation 14

[0152]4-Benzylcarbonyloxy-3-(N-tert-butoxycarbonyl-N-propansulfonylamino)-1-[((2S)-2,3-epoxypropoxy)]benzene

[0153] By carrying out the operation as described in preparation 13 butusing 1-propansulfonyl chloride instead of 1-butansulfonyl chloride, thetitle compound is obtained.

[0154] [α]_(D)=+4.5° C. (c, 1% in ethanol)

[0155] Preparation 15

[0156]4-Benzyloxy-3-(N-methylaminosulfonyl)-1-[((2S)-2,3-epoxypropoxy)]benzene]

[0157] 15a. 2,5-Dihydroxy-N-methylbenzenesulfonamide

[0158] 2.27 g (7.75 mmol) of 4-acetyloxy-2-(chlorosulfonyl)phenylacetate, as obtained according to the process described in J. Am. Chem.Soc., 1951, 73, 2558-2565, are stirred at ambient temperature for 2hours in 8 ml of tetrahydrofuran and 8 ml of a solution of methylamine(77.5 mmol) in methanol. The solvent is evaporated and the residue istaken up in 10 ml of acidified water. Extraction is carried out withethyl acetate, the two phases are separated, the organic phase is driedover sodium sulfate and filtered, and the solvent is evaporated underreduced pressure. Purification is carried out by chromatography on acolumn of silica gel, elution being carried out with a hexane/ethylacetate=1/2 mixture. The title compound is obtained.

[0159] 15b.2-Hydroxy-5-[[tert-butyl(dimethyl)silyl]oxy]-N-methylbenzenesulfonamide

[0160] 1.07 g (7.10 mmol) of tert-butyldimethylsilyl chloride (TBDMSCl)and 1.76 ml of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) are mixed andthis mixture is added to a solution of 1.4 g (6.9 mmol) of the productfrom the preceding stage in 20 ml of methylene chloride and 5 ml oftetrahydrofuran. The mixture is stirred at ambient temperature for 2hours. Washing is carried out with water and with 20 ml of a 5% H₃PO₄solution and, afterwards, with a sodium bicarbonate solution. The twophases are separated, the organic phase is dried over sodium sulfate andfiltered, and the solvent is evaporated under reduced pressure. Thetitle compound is obtained.

[0161] 15c.4-[[tert-Butyl(dimethyl)silyl]oxy]-2-(N-methylaminosulfonyl)phenylBenzoate

[0162] 1.8 g (5.67 mmol) of the product from the preceding stage aremixed under a nitrogen atmosphere in 10 ml of methylene chloride, and1.8 ml of pyridine and 1.3 ml of benzoyl chloride at 0° C. are addedthereto. The mixture is stirred at ambient temperature for 3 hours andthen a sodium bicarbonate solution is added thereto. Extraction iscarried out with ethyl acetate, the two phases are separated, theorganic phase is dried over sodium sulfate and filtered, and the solventis evaporated under reduced pressure. The residue is purified bychromatography on a column of silica gel, elution being carried out witha hexane/ethyl acetate=2/1 mixture. The title compound is obtained.

[0163] 15d. 4-Hydroxy-2-(N-methylaminosulfonyl)phenyl Benzoate

[0164] 1.7 g (4.03 mmol) of the product from the preceding stage aremixed under a nitrogen atmosphere in 80 ml of a 1% solution ofhydrochloric acid in 95% ethanol. The mixture is stirred at ambienttemperature for 3 hours. 100 ml of water are added thereto, extractionis carried out with ethyl acetate, the two phases are separated, theorganic phase is dried over sodium sulfate and filtered, and the solventis evaporated under reduced pressure. The title compound is obtained.

[0165] M.p. 168-170° C.

[0166] 15e.4-Benzyloxy-3-(N-methylaminosulfonyl)-1-[((2S)-2,3-epoxypropoxy)]benzene

[0167] By carrying out the operation as described in preparation 13d butusing the product from the preceding stage instead of the product fromstage 13c, the title compound is obtained.

[0168] [α]_(D)=+19.9° (c=1% in chloroform)

[0169] Preparation 16

[0170] 4-tert-Butoxycarbonylamino-1-(4-cyanophenyl)piperidine

[0171] By carrying out the operation as described in preparation 6 butusing 4-bromocyanobenzene instead of 4-bromo-1-methoxycarbonylbenzene,the title compound is obtained.

[0172] M.p. 188-189° C.

[0173] Preparation 17

[0174] 4-Amino-1-(4-cyanophenyl)piperidine

[0175] By carrying out the operation as described in preparation 5 butusing the product from preparation 16 instead of the product frompreparation 4. The base is released with ammonia and extraction withethyl acetate, the title compound is obtained.

[0176] M.p. 78-80° C.

[0177] Preparation 18

[0178]4-tert-Butoxycarbonylaminomethyl-1-(4-ethoxycarbonylphenyl)piperidine

[0179] By carrying out the operation as described in preparation 4 butusing 4-(tert-butoxycarbonylaminomethyl)piperidine (disclosed in WO99/65895) instead of the 4-(tert-butoxycarbonylamino)piperidine ofpreparation 1, the title compound is obtained.

[0180] Preparation 19

[0181] 4-Aminomethyl-1-(4-ethoxycarbonylphenyl)piperidine Hydrochloride

[0182] By carrying out the operation as described in preparation 5 butusing the product from preparation 18 instead of the product frompreparation 4, the title compound is obtained.

[0183] Preparation 20

[0184]4-Benzyloxy-3-(N-benzyloxycarbonyl-N-methansulfonylamino)-1-[((2S)-2,3-epoxypropoxy)]benzene

[0185] 20a.4-Benzyloxy-3-(N-benzyloxycarbonyl-N-methansulfonylamino)benzene Acetate

[0186] 1 g (0.003 mol) of 4-benzyloxy-3-(methan- sulfonylamino)benzeneacetate (WO 96/04233) in 20 ml of methylene chloride, 0.50 ml (0.0033mol) of 95% benzyl chloroformate, 0.006 g of dimethylaminopyridine and0.46 ml (0.0033 mol) of triethylamine is stirred at 50° C. for 10 hours.The solvent is evaporated, the residue is taken up in methylenechloride, washing with water is carried out, the two phases areseparated, the organic phase is dried over sodium sulfate and filtered,and the solvent is evaporated under reduced pressure. Purification iscarried out by chromatography on a column of silica gel, elution beingcarried out with ethyl acetate. The title compound is obtained.

[0187] M.p. 140-142° C.

[0188] 20b.4-Benzyloxy-3-(N-benzyloxycarbonyl-N-methansulfonylamino)phenol

[0189] By carrying out the operation as described in preparation 13c butusing the product from the preceding stage instead of the product frompreparation 13b, the title compound is obtained.

[0190] M.p. 138-140° C.

[0191] 20c.4-Benzyloxy-3-(N-benzyloxycarbonyl-N-methansulfonylamino)-1-[((2S)-2,3-epoxypropoxy)]benzene

[0192] By carrying out the operation as described in preparation 13d butusing the product from the preceding stage instead of the product fromstage 13c, the title compound is obtained.

[0193] M.p. 78-80° C.; [α]_(D)=+4.4° (c=0.5% in methanol)

[0194] Preparation 21

[0195] 4-Amino-1-(4-tert-butoxycarbonylphenyl)piperidine

[0196] 1.5 g (7.5 mmol) of 4-(2,5-dimethylpyrrol-1-yl)piperidine, 60 mlof dimethylformamide and 1.6 g (7.5 mmol) of the tert-butyl ester of4-fluorobenzoic acid and 2.6 ml of diisopropylethylamine are mixed undernitrogen. The mixture is heated with stirring for 6 hours at 90° C. andafterwards is stirred at ambient temperature for 15 hours. 1.04 g (7.5mmol) of potassium carbonate are added thereto and the mixture is heatedat 90° C. for 5 days. The mixture is poured into water, extraction iscarried out with ethyl acetate and washing is carried out with water.The two phases are separated, the organic phase is dried over sodiumsulfate and filtered, and the solvent is evaporated under reducedpressure. Purification is carried out by chromatography on a column ofsilica gel, elution being carried out with a hexane/ethyl acetate=3/1mixture.4-(2,5-Dimethylpyrrol-1-yl)-1-(tert-butoxycarbonylphenyl)piperidine isisolated. 250 mg of NH₂OH.HCl and 0.7 ml of ethanol are mixed undernitrogen and stirred for 30 minutes. 67 mg (1.2 mmol) of KOH in 0.3 mlof a 1/1 ethanol/water solution and 300 mg (0.084 mmol) of the aboveintermediate product in 0.5 ml of ethanol are added thereto. The mixtureis heated at 80° C. for 12 hours. Extraction is carried out with ethylacetate, KOH is added to the aqueous phase until a pH of 9 is achieved,and extraction is carried out with ethyl acetate. The two phases areseparated, the organic phase is dried over sodium sulfate and filtered,and the solvent is evaporated under reduced pressure. The title compoundis obtained.

[0197] M.p. 89-91° C.

[0198] Preparation 22

[0199] 4-tert-Butoxycarbonylamino-1-(4-aminocarbonylphenyl)piperidine

[0200] By carrying out the operation as described in preparation 4 butusing 4-fluorobenzamide instead of 4-ethoxycarbonyl-1-fluorobenzene, thetitle compound is obtained.

[0201] M.p. >270° C.

[0202] Preparation 23

[0203] 4-Amino-1-(4-aminocarbonylphenyl)piperidine Hydrochloride

[0204] By carrying out the operation as described in preparation 5 butusing the product from preparation 22 instead of the product frompreparation 4, the title compound is obtained.

EXAMPLE 1

[0205]3-[1-(4-Ethoxycarbonylphenylmethyl)piperidin-4-yl-amino]-1-(4-hydroxyphenoxy)-2-propanol

[0206] 1a.3-[1-(4-Ethoxycarbonylphenylmethyl)piperidin-4-ylamino]-1-(4-methoxyethoxymethoxyphenoxy)-2-propanol

[0207] 0.86 g (0.0033 mol) of4-(methoxyethoxymethoxy)-1-(2,3-epoxypropoxy)benzene and 0.83 g (0.0033mol) of the product obtained in preparation 3 in the free base form areheated at reflux for 17 hours in 40 ml of ethanol. The solvent isevaporated under reduced pressure and the product is dried. The crudereaction product is purified by flash chromatography, elution beingcarried out with methanol. The product is crystallized from isopropylether.

[0208] M.p. 73-75° C.

[0209] 1b.3-[1-(4-Ethoxycarbonylphenylmethyl)piperidin-4-yl-amino]-1-(4-hydroxyphenoxy)-2-propanolDioxalate

[0210] A mixture comprising 0.7 g (0.0014 mol) of the product obtainedin the preceding stage and 1.1 ml (0.014 mol) of CF₃COOH in 40 ml ofmethylene chloride is heated at 40° C. for 8 hours. The solvent isevaporated and ammonia is added. Extraction is carried out with ethylacetate, the extract is dried and the solvent is evaporated. The crudereaction product is purified by flash chromatography, elution beingcarried out with methylene chloride/methanol=9:1. The title compound isobtained in the base form. Its dioxalate is prepared using oxalic acidin acetone.

[0211] M.p. 180-184° C. (dioxalate)

EXAMPLE 2

[0212]3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]1-1(4-hydroxyphenoxy)-2-propanol

[0213] 2a.3-[1-(4-Ethoxycarbonylphenyl)piperidinylamino]-1-(4-benzyloxyphenoxy)-2-propanol

[0214] 1.03 g (0.004 mol) of the product from preparation 9 and 1 g(0.004 mol) of the product from preparation 5 in the base form areheated at reflux for 20 hours in 50 ml of ethanol. The solvent isevaporated and the crude reaction product is purified by flashchromatography, elution being carried out with the CH₂Cl₂/methanol=9:1mixture. The title product is obtained.

[0215] M.p. 112-114° C.

[0216] 2b.3-[1-(4-Ethoxycarbonylphenylmethyl)piperidin-4-ylamino]-1-(4-hydroxyphenoxy)-2-propanol

[0217] 1.15 g (0.0023 mol) of the product from the preceding stage arehydrogenated at 40° C. in 20 ml of ethanol +20 ml of THF in the presenceof 0.1 g of 10% palladium-on-carbon at ambient pressure for eight hours.150 ml of hydrogen are absorbed.

[0218] The mixture is filtered and the solvent is evaporated. Theresidue is crystallized from ethyl acetate. The title product isobtained.

[0219] M.p. 158-161° C.

EXAMPLE 3

[0220]3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-2-propanoland Its (2S) Isomer

[0221] 3a.3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-benzyloxy)-3-(methansulfonylamino)phenoxy]-2-propanol

[0222] 1 g (0.004 mol) of the product from preparation 5 in the baseform is mixed with 1.35 g (0.003 mol) of the product from preparation 7and 0.2 g of lithium perchlorate in 50 ml of CH₃CN. The mixture is leftstirring for 24 hours at ambient temperature and is then heated at 400for eight hours.

[0223] The solvent is evaporated and the product thus obtained istreated at 40° C. for eight hours with a solution of hydrochloric acidin ethyl acetate. The solvent is evaporated, the residue is treated withan NaHCO₃ solution and extraction is carried out with ethyl acetate. Thesolvent is again evaporated and the crude reaction product is purifiedby flash chromatography, elution being carried out with aCH₂Cl₂/methanol=9:1 mixture. The title product is obtained.

[0224] M.p. 130-132° C.

[0225] 3b.3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-2-propanol

[0226] 0.8 g (0.0013 mol) of the product from the preceding stage aresubjected to hydrogenation in the presence of 0.1 g ofpalladium-on-carbon (10%) in 15 ml of ethanol+15 ml of THF. Afterreacting for eight hours at 400 and at ambient pressure, the mixture isfiltered and the solvent is evaporated. The crude reaction product ispurified by flash chromatography, elution being carried out with aCH₂Cl₂/methanol=9:1 mixture. The title product is obtained and iscrystallized from isopropanol.

[0227] M.p. 140-143° C.

[0228] Isomer (2S)

[0229] By carrying out the operation according to the above stages 3aand 3b but using the product from preparation 7 in the optically active(2S) form, the (2S) enantiomer of the title compound is obtained.

[0230] M.p. 96-99° C. (hydrated form).

EXAMPLE 4

[0231]3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methysulfinyl)phenoxy]-2-propanoland Its (2S) Isomer

[0232] 4a.3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-benzyloxy)-3-(methysulfinyl)phenoxy]-2-propanol

[0233] 0.8 g (0.0032 mol) of the product from preparation 5 in the baseform is heated at reflux overnight with 1 g (0.0031 mol) of the productfrom preparation 8 in 50 ml of ethanol. The solvent is evaporated andthe crude reaction product is purified by flash chromatography, elutionbeing carried out with a CH₂Cl₂/methanol=95:5 mixture. The title productis obtained.

[0234] M.p. 135-137° C.

[0235] 4b.3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methysulfinyl)phenoxy]-2-propanoltrifluoroacetate

[0236] 0.98 g (0.0017 mol) of the product from the preceding stage isheated at 55° C. for seven hours in 20 ml of CF₃COOH. The solvent isevaporated, a bicarbonate solution is added and extraction is carriedout with ethyl acetate. The solvent is evaporated and the crude reactionproduct is purified by flash chromatography, elution being carried outwith a CH₂Cl₂/methanol=9:1 mixture. The title product is obtained.

[0237] M.p. 78-80° C. (trifluoroacetate).

EXAMPLE 5

[0238]3-[1-(4-N-Butylaminocarbonylphenyl)piperidinylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-(2S)-2-propanol

[0239] 5a.3-[1-(4-N-Butylaminocarbonylphenyl)piperidinylamino]-1-[(4-benzyloxy)-3-(methansulfonylamino)phenoxy]-(2S)-2-propanol

[0240] 0.72 g (0.0026 mol) of the product from preparation 11b in thebase form is heated at reflux overnight with 1.08 g (0.0024 mol) of theproduct from preparation 7 in 25 ml of ethanol. The solvent isevaporated and the crude reaction product is purified by flashchromatography, elution being carried out with methanol. The productthus obtained is treated at 70° for 4 hours with a solution ofhydrochloric acid in ethyl acetate. The solvent is evaporated, theresidue is treated with an NaHCO₃ solution and extraction is carried outwith ethyl acetate. The solvent is again evaporated. The title productis obtained.

[0241] M.p. 123-133° C.

[0242] 5b.3-[1-(4-N-Butylaminocarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-(2S)-2-propanol

[0243] By carrying out the operation as described in example 3b butusing the product from the preceding stage instead of the product fromstage 3a, the title compound is obtained.

[0244] M.p. 146-148° C.

EXAMPLE 6

[0245]3-[1-(4-N,N-Diethylminocarbonylphenyl)piperidiny-4-ylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]]-(2S)-2-propanol

[0246] By carrying out the operation as described in example 5 but usingthe product from preparation 12b in the base form instead of the productfrom preparation 11b, the title compound is obtained.

[0247] M.p. 67-70° C.

EXAMPLE 7

[0248]3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(N-butansulfonylamino)phenoxy]-(2S)-2-propanoland Its Hydrochloride

[0249] By carrying out the operation as described in example 5 but usingthe product from preparation 13d instead of the product from preparation7 and the product from preparation 5 in the base form instead of theproduct from preparation 11b, the title compound is obtained. Thehydrochloride is prepared using ethyl acetate and hydrochloric acid.

[0250] M.p. 192-195° C. (hydrochloride).

EXAMPLE 8

[0251]3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(N-propansulfonylamino)phenoxy]-(2S)-2-propanol

[0252] By carrying out the operation as described in example 5 but usingthe product from preparation 14 instead of the product from preparation7 and the product from preparation 5 in the base form instead of theproduct from preparation 11b, the title compound is obtained.

[0253] M.p. 63-65° C.

EXAMPLE 9

[0254]3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methylaminosulfonyl)phenoxy]-(2S)-2-propanol

[0255] 0.56 g (0.0015 mol) of the product from preparation 15e is heatedat reflux overnight with 0.38 g (0.0015 mol) of the product frompreparation 5 in the base form in 10 ml of DMF. The solvent isevaporated and the crude reaction product is purified by flashchromatography, elution being carried out with methanol. The titleproduct is obtained.

[0256] M.p. 87° C.

EXAMPLE 10

[0257]3-[1-(4-Cyanophenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(N-methansulfonylamino)phenoxy]-(2S)-2-propanol

[0258] By carrying out the operation as described in example 5 but usingthe product from preparation 17 instead of the product from preparation11b, the title compound is obtained.

[0259] M.p. 78-80° C.

EXAMPLE 11

[0260]3-[1-(4-tert-Butoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(N-methansulfonylamino)phenoxy]-(2S)-2-propanol

[0261] By carrying out the operation as described in example 3 but usingthe product from preparation 21 instead of the product from preparation5 and the product from preparation 20 instead of the product frompreparation 7, the title compound is obtained.

EXAMPLE 12

[0262]3-[[1-(4-Ethoxycarbonylphenyl)-4-piperidinylmethyl]-amino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-(2S)-2-propanol

[0263] By carrying out the operation as described as for example 5 butusing the product from preparation 19 instead of the product frompreparation 11b, the title compound is obtained.

EXAMPLE 13

[0264]5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxyphenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

[0265] 13a. 5-Amino-2-(4-tert-butoxycarbonylaminopiperidino)pyridine

[0266] 2 g (0.0062 mol) of5-nitro-2-(4-tert-butoxycarbonylpiperidino)pyridine are mixed in 40 mlof ethanol and 60 ml of tetrahydrofuran. 0.4 g of 10% Pd/C are added andhydrogenation is carried out at 40° C. at ambient pressure for 7 hours.The mixture is filtered, the solvent is evaporated and 2 g of the titlecompound are obtained in the solid form.

[0267] 13b.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-tert-butoxycarbonylaminopiperidino)pyridine

[0268] 0.4 g (0.0013 mol) of the product from the preceding stage isdissolved in 10 ml of pyridine. 0.3 g (0.0013 mol) of4-isopropylbenzenesulfonyl chloride is added thereto and the mixture isheated at 50° C. for 2 hours. The solvent is evaporated (with theprecautions for hydrochloric acid) and the residue is taken up in ethylacetate and water. The two phases are separated, the organic phase iswashed with water and dried, and the solvent is evaporated under reducedpressure. Purification is carried out by flash chromatography on acolumn of silica gel, elution being carried out with a cyclohexane/ethylacetate=6/4 mixture. The title product is obtained.

[0269] M.p. 208-209° C.

[0270] 13c.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-aminopiperidino)pyridinedihydrochloride

[0271] 2.1 g (0.0042 mol) of the product from the preceding stage areheated to reflux for 4 hours in 20 ml of ethyl acetate and 20 ml of anapproximately 3N solution of gaseous hydrochloric acid in ethyl acetate.The solvent is evaporated under reduced pressure, the residue is takenup in acetone and filtered, the precipitate is washed with acetone and1.8 g of the title product are obtained, which product is crystallizedfrom ethanol.

[0272] M.p. 270-273° C.

[0273] 13d.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-(benzyloxy)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

[0274] 0.239 g (0.932 mol) of 4-benzyloxy-1-(2,3-epoxypropoxy)benzeneand 0.35 g (0.935 mmol) of the product from the preceding stage in thebase form are heated at reflux for 20 hours in 10 ml of ethanol. Thesolvent is evaporated under reduced pressure and purification is carriedout by flash chromatography on a column of silica gel, elution beingcarried out with a methylene chloride/methanol=95/5 mixture. 0.37 g ofthe title product is obtained in the form of a glassy product.

[0275] 13e.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxyphenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

[0276] 0.37 g (0.586 mmol) of the product from the preceding stage, 10ml of ethanol, 10 ml of tetrahydrofuran and 0.037 g of 10% Pd/C aremixed. Hydrogenation is carried out at 40° C. and ambient pressure for 8hours. The mixture is filtered, the solvent is evaporated under reducedpressure and the residue is purified by flash chromatography on a columnof silica gel, elution being carried out with a 9/1 methylenechloride/methanol mixture. The title product is obtained.

[0277] M.p. 75-78° C.

EXAMPLE 14

[0278] 14a.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-benzyloxy)-3-(methylsulfinyl)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

[0279] 0.27 g (0.00084 mol) of4-benzyloxy-3-methylsulfinyl-1-[(2,3-epoxypropoxy)]benzene (preparedaccording to U.S. Pat. No. 4,396,629/example 3) and 0.33 g (0.00088 mol)of the product from example 13c) in the base form are heated at refluxovernight in 10 ml of ethanol. The solvent is evaporated and the crudereaction product is purified by flash chromatography, elution beingcarried out with a CH₂Cl₂/methanol 9/1 mixture. The title product isobtained in the form of a glassy solid.

[0280] 14b.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3-(methylsulfinyl)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

[0281] 0.4 g (0.0006 mol) of the product from the preceding stage isheated at 55° C. for 5 hours in 10 ml of CF₃COOH. The solvent isevaporated under reduced pressure, the crude product is dissolved inethyl acetate, washing is carried out using a saturated aqueousbicarbonate solution and drying is carried out. The product thusobtained is purified by flash chromatography, elution being carried outwith a CH₂Cl₂/methanol=9/1 mixture and then with a CH₂Cl₂/methanol=85/15mixture. The title product is obtained.

[0282] M.p.: 128-130° C.

EXAMPLE 15

[0283]5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3-methansulfonylamino)phenoxy)-(2S)-2-hydroxypropyl)amino)piperidino)pyridine

[0284] By carrying out the operation as described in example 5 but usingthe product from example 13c in the base form instead of the productfrom preparation 11b, the title compound is obtained.

EXAMPLE 16

[0285]5-[((4-Bromophenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3-(methylsulfinyl)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

[0286] 16a.5-[((4-Bromophenyl)sulfonyl)amino]-2-[4-(tert-butoxycarbonylamino)piperidino]pyridine

[0287] By carrying out the operation as in example 13b but using4-bromobenzenesulfonyl chloride instead of 4-isopropylbenzenesulfonylchloride, the title compound is obtained.

[0288] 16b.5-[((4-Bromophenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3-(methylsulfinyl)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

[0289] By carrying out the operation as in example 13c, the product fromthe preceding stage is deprotected. 1.2 g [lacuna] this product, 1.12 mlof triethylamine and 0.738 g of4-benzyloxy-3-methylsulfinyl-1-[(2,3-epoxypropoxy)]benzene (preparedaccording to U.S. Pat. No. 4,396,629/example 3) are heated at reflux for12 hours in 100 ml of ethanol. The solvent is evaporated andpurification is carried out by flash chromatography, elution beingcarried out with a CH₂Cl₂/methanol/NH₃=90/10/1 mixture. A mixturecontaining 680 mg of the product thus obtained and 30 ml of CF₃COOH isheated at 55° C. for 5 hours. The solvent is evaporated and the residueis treated with a saturated sodium bicarbonate solution. Extraction iscarried out with ethyl acetate, the extract is dried and the solvent isevaporated. The crude reaction product is purified by flashchromatography, elution being carried out with methylenechloride/methanol/NH₃90/10/1. The title compound is obtained in the baseform.

[0290] M.p. 147° C.

EXAMPLE 17

[0291]3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-(4-hydroxy-3-(methylsulfonyl)phenoxy)-(2S)-2-propanol

[0292] By carrying out the operation as described in example 14 butusing 4-benzyloxy-3-methylsulfonyl-1-((2S)-2,3-epoxypropoxy)benzene(disclosed in WO 99/65895, ex. 67) instead of4-benzyloxy-3-methylsulfinyl-1-[(2,3-epoxypropoxy)]benzene and theproduct from preparation 5 in the base form instead of the product fromexample 13c), the title compound is obtained.

[0293] M.p. 83-85° C.; [α]_(D)=+1.00 (c=1% in methanol)

EXAMPLE 18

[0294]3-[1-[4-((4-Isopropylphenyl)sulfonylamino)phenyl]-piperidinylamino]-1-(4-hydroxy-3-(methansulfonylamino)phenoxy)-(2S)-2-propanol

[0295] By carrying out the operation as described in example 5 but using4-amino-1-[4-((4-isopropylphenyl)sulfonylamino)phenyl]piperidine insteadof the product from preparation 11b, the title compound is obtained.

[0296] M.p. 90-93° C.

EXAMPLE 19

[0297]3-[1-[4-((4-Bromophenyl)sulfonylamino)phenyl]-piperidinylamino]-1-(4-hydroxy-3-(methansulfonylamino)phenoxy)-(2S)-2-propanol

[0298] 0.95 g (0.0023 mol) of4-amino-1-[4-((4-bromophenyl)sulfonylamino)phenyl]piperidine and 1.1 g(0.0024 mol) of the product from preparation 7, (2S) isomer, are heatedunder reflux for 12 hours in 100 ml of ethanol. The solvent isevaporated and purification is carried out by flash chromatography,elution being carried out with a CH₂Cl₂/methanol=80/20 mixture. Amixture containing 680 mg of the product thus obtained and 30 ml ofCF₃COOH is heated at 55° C. for 5 hours. The solvent is evaporated andthe residue is treated with a saturated sodium bicarbonate solution.Extraction is carried out with ethyl acetate, the extract is dried andthe solvent is evaporated. The crude reaction product is purified byflash chromatography, elution being carried out with methylenechloride/methanol 90/10. The title compound is obtained.

[0299] M.p. 105-108° C.

1. A compound of formula (I)

where R₁ represents a hydrogen or halogen atom or an—S(O)_(z)—(C₁-C₄)alkyl, —S(O)_(z)—(C₁-C₄)R₃, —SO₂—NH—(C₁-C₄)alkyl,—NHCO(C₁-C₄)alkyl, —CO(C₁-C₄)alkyl or —NHSO₂—(C₁-C₄)alkyl group; m and nindependently represent 0, 1 or 2; A represents a group of formula (a)or (b):

where x is N or CH; R₂ represents an —SO₂—R₃, —CO—R₃ or—CO—(C₁-C₄)—alkyl group; R₃ represents a phenyl group, optionallysubstituted by a (C₁-C₄)alkyl or (C₁-C₄)alkoxy group, one or two halogenatoms or a heterocycle; R₄ represents a hydrogen or halogen atom or a(C₁-C₆)alkyl, (C₁-C₄)alkoxy, —COOH, —COO(C₁-C₄)alkyl, —CN, —CONR₅R₆,—NO₂, —NHSO₂(C₁-C₄)alkyl or —SO₂NR₅R₆ group; z is 1 or 2; R₅ and R₆independently represent a hydrogen atom or a (C₁-C₄)alkyl, phenyl orphenyl(C₁-C₄)alkyl group; and its salts or solvates.
 2. The compound asclaimed in claim 1, where A is a group (a), X is N and the NHR₂ group isin the 5 position of the pyridine.
 3. The compound as claimed in claim1, where n and m are zero.
 4. The compound as claimed in claim 1, wherethe (C₁-C₄)alkyl group is a methyl or ethyl group.
 5. The compound asclaimed in claim 1, where A is a group (b) and the R₄ group is in the 4position of the benzene.
 6. The compound as claimed in claim 1, where Ais a group (b) and R₄ is chosen from —COOH, —COO(C₁-C₄)alkyl, —CN, —NO₂,—CONR₂R₃, —NHSO₂— (C₁-C₄) alkyl and —SO₂NR₅R₆.
 7. A process for thepreparation of the compounds of formula (I), characterized in that acompound of formula (II)

in which R₁ is as indicated in claim 1, P′ is a protective group and Lis a group of formula (c) or (d)

where Gp is a leaving group, is reacted with an amine of formula (III)

in which n and m are as defined in claim 1, the group P′ being cleavedand the compound of formula (I) thus obtained optionally being convertedinto one of its salts.
 8. A pharmaceutical composition comprising, asactive principle, the compound as claimed in claims 1 to
 6. 9. The useof the compound as claimed in claims 1 to 6 for the preparation ofmedicaments indicated in irritable bowel syndrome (IBD), or with amodulating effect on intestinal motricity, a lipolytic effect, anantiobesity effect, an antidiabetic effect, a psychotropic effect, anantiglaucoma effect, a cicatrizant effect, an antidepressant effect or atocolytic effect.
 10. A compound of formula (III′)

where n, m, X and R₂ are as defined in claim 1, and its salts orsolvates.
 11. A compound of formula (III″)

where P° is a tert-butoxycarbonyl group; n and m are 0, 1 or 2; R°₄ is agroup chosen from —COOH, —COO(C₁-C₄)—alkyl, —CONR°₅R°₆ and—NHSO₂(C₁-C₄)alkyl; R°₅ and R°₆ independently represent a hydrogen atomor a (C₁-C₄)alkyl group; and its salts or solvates.